Background: Advanced esophageal squamous cell cancer (ESCC) is frequently diagnosed in elderly patients (pts) and impact of 2nd line chemotherapy is poorly defined. In line with recent data demonstrating effectiveness of checkpoint inhibitors Nivolumab (Nivo) and Ipilimumab (Ipi) in squamous cell carcinoma pts, combined Nivo/Ipi therapy will be assessed as 2nd line therapy of advanced ESCC in elderly pts. Methods: RAMONA is a multicenter open-label phase II trial (NCT03416244). Eligibility and geriatric status of the pts will be assessed by the G8 screening tool and the Deficit Accumulation Frailty Index (DAFI). Upon safety assessment after a three cycle run-in phase of Nivo (240 mg Q2W), eligible pts will be escalated to Nivo (240 mg Q2W)/Ipi (1 mg/kg Q6W) combination therapy. The other pts will remain on Nivo only. The primary objective of this trial is to demonstrate a significant survival benefit of the Nivo/Ipi combination therapy in advanced ESCC compared to historical data of standard chemotherapy regimens. Primary endpoint is overall survival (OS); secondary endpoints are tumor response, PFS, safety and quality of life (QoL). The trial has a 90% Power to detect a hazard ratio of 0.68 at a one-side significance level of alpha = 0.05 under the assumption of exponential survival. This corresponds to an increase of the 1-year OS rate by a margin of 13% compared to historical controls for standard chemotherapy (i.e. 30% vs 17%). Subjects are accrued for a period of 12 month. Follow-up continues for 24 month after the last subject is added. Including a sample size increase to compensate for uninformative drop-outs a total of n = 75 subjects will be recruited. The primary endpoint will be assessed using a one-sample log-rank test. A particular study objective is the evaluation of the tolerability of Nivo as single agent and in combination with Ipi in terms of QoL. Therefore time to QoL deterioration will be determined. 18 pts have been enrolled by mid of September 2018. RAMONA also includes translational research to identify predictive biomarkers, establish organoid cultures from tumor tissues and assess the utility of microbiome analyses for response prediction. Clinical trial information: NCT03416244